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Genetic imprinting
Introduction Epigenetic modifications are still being uncovered and are associated with many important functions within the mammalian genome. They are known to be important in the stability and proper segregation of chromosomes during mitosis, regulation of silencing repetitive elements, and regulation of activation and repression of genes and gene clusters. The current reasoning for epigenetic modification is the diverse differentiation of cells, cells need to pass on genetic information during division. DNA methylation and histone modifications are the two most well-known mechainisms of epigenetics. Non-coding RNAs and nucleosomal postioning have been suggested modifications but may be more like facilitators 1. DNA methylation is a modification where a methyl group is added predominately cytosines and specifically CpG dinucleotides. Stretches of CpG repeats are relatively rare within the genome. Repeats in the genome are known as CpG islands which are generally before promoters, these regions generally remain unmethylated; but the other CpG dinucleotides are methylated. There is still a lot more to understand about DNA methylation. Post-translational histone modifications are a complex set of modifications that are only beginning to be understood. For the sake of this article these modifications can activate or repress expression 1. Genetic imprinting is a form of epigenetics in which only one allele is expressed for a particular gene. Therefore either the paternal or maternal genetic information is expressed. Imprinted genes are generally located in clusters and regulated by a single imprinting coding region (ICR). 1 The clusters range from 100 kb to 1 MB 4. The known imprinted genes are involved in fetal and placental development and a variety of post-natal processes. 1,2 So, why do we have genetic imprinting? This interesting form of epigenetics exposes recessive alleles for expression. Evolution Even though an organisms fitness is a stake genetic imprinting has been conserved for millions of years (figure 1). It has been suggested that imprinting arose from the host-defense machinery because it involves Cytosine methyltransferases which are used to silence foreign DNA. This idea is further supported because of the large repeating segments in imprinted regions, likely arising from transposons. It has further been shown that evolutionary pressure on maternally inherited genes (MEGs) and paternally inherited genes (PEGs) have different evolutionary pressures suggesting that they have different regulation. It also appears that marsupials and eutherians have different regions imprinted with eutherians having more imprinted clusters. This suggests convergent evolution. eutherians may have more imprinted genes because they have a longer gestation period 3. There have been two proposed theories as to why imprinting has been selected for: Kinship The Kinship theory suggests that genetic imprinting occurs to increase the rate of survival of both parents genes. The idea behind this theory is that one mother can have offspring from many fathers, therefore all the siblings share the same amount of genetic similarity to the mother but may differ from the father. The father wants his paternal genetic material to have the highest rate of survival and doesn't care about the other siblings or mothers needs. But the mother wants the offspring to take as little from her as possible to be able to reproduce again. Hence many of the imprinted genes somehow regulate/are involved in pre- and post-natal growth. The paternal genes result in increased growth and the maternal genes decreased growth 2,3. This is probably the most widely supported theory but there are some criticisms: # It has failed to predict silencing and/or expression at certain loci # It does not account for the abundance of maternal expressed genes over paternal expressed genes 2 Maternal-offspring Coadaptation This theory can help explain the later criticism of the Kinship theory. The idea here is that it is in the offsprings best interest to be more like the mother, when the mother provides long term post-natal care. Therefore, there would be more maternal genes expressed than paternal. Again, there are some criticism such as, more paternally expressed genes in reciprocal hybrids and this theory would lead to loss of genetic imprinting 2,3. Genetic imprinting is probably a mix between these two theories as well as others. There have been many other proposed theories but these are the most widely accepted 2. Mechanism The common epigenetic mechanisms are involved in genetic imprinting. These mechanisms are still being investigated but there are some clues as to how they work. ICR's are specific to parental alleles, thus the paternal ICR is different from maternal. DNA methylation has been shown to be necessary for genetic imprinting by knocking out the primary enzyme that methylates DNA in mice 2. During fertilization of the egg, the epigenetic modifications of the inherited DNA strands are "erased", but the methylation at the ICRs remains (figure 2A) 1,2,3. Later in development these regions are reprogrammed. Genetic imprinting is involved in both activation and repression of genes,where a methylated ICR is inactive. An unmethylated ICR is active and will result in genetic imprinting (Figure 2B) 1,2,3. It seems that imprinted genes by methylation have less selective pressure because they are found in the embryo, placenta and adult tissues. Histone modifications seem to control the genes that have more selective pressure because they are generally found in only the embryo or only the placenta in mice. Mice have a more positive pressure to keep than human because of the liter size. Human babies tend to be the only fetus and thus don't need to fight liter mates to survive 3. Histone modifications can effect DNA methylation as well as imprinting (figure 2E) 1. There are two proposed mechanisms for regulation of ICRs: long non coding RNAs (lncRNA), and gene insulation. All but one gene cluster codes for at least one lncRNA suggesting this mechanism is used quite often. The mechanism by which lncRNA works is still being researched but the transcription of the lncRNA inhibits the transcription of the coding gene (figure 2F). Insulation is when enhancers are physically blocked from binding to DNA thus inhibiting expression. This can be from a a protein binding or from forming a hairpin loop in the DNA (figure 2C) 1,2. Human disorders The genes encoded in the genetic imprinting clusters are involved in cellular processes controlling metabolism and body temperature regulation. There are also a large number of imprinted genes in the brain, this can lead to neurological and behavior disabilities, generally shown later in life. In mice it has been shown the imprinting effects milk release, maternal care, neurogenisis, sleep, memory and cognition and social behavior. In pups it effects suckling (usually from poor muscle tone), activity, and communication 4. The table below highlights a few disorders associated with genetic imprinting. Increased tumor growth has also been associated with certain genetic imprinting disorders. References 1.Adalsteinsson, B.T. and Ferguson-Smith, A.C. 2014. Epigenetic Control of the Genome—Lessons from Genomic Imprinting. Genes. 5:635-655. PMID:25257202 2. Peters, J. 2014. The role of genetic imprinting in biology and disease: expanding the view. Nature Reviews. 15:517-530. PMID:24958438 3. Pires, N.D. and Grossniklaus U. 2014. Different yet similar: evolution of imprinting in flowering plants and mammals. F1000Prime Reports. 6:63 PMID:25165562 4. Peters, J. 2009. Overview of mammalian genome special issue on epigenetics. Mamm Genome. 20:529-31. PMID:19862571